Infectious Disease

Ferdinands, J.M., Gaglani, M., Ghamande, S., Martin, E.T., Middleton, D., Monto, A.S., Silveira, F., Talbot, H.K., Zimmerman, R., Smith, E.R. and Patel, M. (2021). “Vaccine Effectiveness Against Influenza-Associated Hospitalizations Among Adults, 2018-2019, US Hospitalized Adult Influenza Vaccine Effectiveness Network.” J Infect Dis 224(1): 151-163.

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We estimated vaccine effectiveness (VE) for prevention of influenza-associated hospitalizations among adults during the 2018-2019 influenza season. Adults admitted with acute respiratory illness to 14 hospitals of the US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) and testing positive for influenza were cases; patients testing negative were controls. VE was estimated using logistic regression and inverse probability of treatment weighting. We analyzed data from 2863 patients with a mean age of 63 years. Adjusted VE against influenza A(H1N1)pdm09-associated hospitalization was 51% (95% confidence interval [CI], 25%-68%). Adjusted VE against influenza A(H3N2) virus-associated hospitalization was -2% (95% CI, -65% to 37%) and differed significantly by age, with VE of -130% (95% CI, -374% to -27%) among adults 18 to ≤56 years of age. Although vaccination halved the risk of influenza A(H1N1)pdm09-associated hospitalizations, it conferred no protection against influenza A(H3N2)-associated hospitalizations. We observed negative VE for young and middle-aged adults but cannot exclude residual confounding as a potential explanation.

Magombedze, G., Pasipanodya, J.G. and Gumbo, T. (2021). “Bacterial load slopes represent biomarkers of tuberculosis therapy success, failure, and relapse.” Commun Biol 4(1): 664.

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There is an urgent need to discover biomarkers that are predictive of long-term TB treatment outcomes, since treatment is expense and prolonged to document relapse. We used mathematical modeling and machine learning to characterize a predictive biomarker for TB treatment outcomes. We computed bacterial kill rates, γ(f) for fast- and γ(s) for slow/non-replicating bacteria, using patient sputum data to determine treatment duration by computing time-to-extinction of all bacterial subpopulations. We then derived a γ(s-)slope-based rule using first 8 weeks sputum data, that demonstrated a sensitivity of 92% and a specificity of 89% at predicting relapse-free cure for 2, 3, 4, and 6 months TB regimens. In comparison, current methods (two-month sputum culture conversion and the Extended-EBA) methods performed poorly, with sensitivities less than 34%. These biomarkers will accelerate evaluation of novel TB regimens, aid better clinical trial designs and will allow personalization of therapy duration in routine treatment programs.

van Zyl, J.S., Felius, J., Alam, A., Hall, S.A., Jamil, A.K., Spak, C.W. and Gottlieb, R.L. (2021). “Dynamic albumin values as clinical surrogate for COVID-19 therapeutics.” J Investig Med May 28;jim-2021-001895. [Epub ahead of print].

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We studied patients admitted for management of COVID-19. Thus, dynamic changes clearly reflect COVID-19 disease. We posited that albumin levels fall dynamically due to the hyperinflammatory pathophysiology of COVID-19, with attendant capillary leak.2 We are delighted that the author of the above letter shares our burning question: does the dynamic fall of serum albumin track the hyperinflammatory markers of C-reactive protein, ferritin, and interleukin 6 (IL-6), and do immunomodulators such as glucocorticoids or anti-IL-6 receptor or anti-IL-6 cytokine monoclonal antibody therapies reverse this? This is an important avenue for future investigation. As IL-6 values are not routinely measured, that question can only be addressed prospectively.[No abstract; excerpt from article].

Taylor, P.C., Adams, A.C., Hufford, M.M., de la Torre, I., Winthrop, K. and Gottlieb, R.L. (2021). “Neutralizing monoclonal antibodies for treatment of COVID-19.” Nat Rev Immunol 21(6): 382-393.

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Several neutralizing monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and are now under evaluation in clinical trials. With the US Food and Drug Administration recently granting emergency use authorizations for neutralizing mAbs in non-hospitalized patients with mild-to-moderate COVID-19, there is an urgent need to discuss the broader potential of these novel therapies and to develop strategies to deploy them effectively in clinical practice, given limited initial availability. Here, we review the precedent for passive immunization and lessons learned from using antibody therapies for viral infections such as respiratory syncytial virus, Ebola virus and SARS-CoV infections. We then focus on the deployment of convalescent plasma and neutralizing mAbs for treatment of SARS-CoV-2. We review specific clinical questions, including the rationale for stratification of patients, potential biomarkers, known risk factors and temporal considerations for optimal clinical use. To answer these questions, there is a need to understand factors such as the kinetics of viral load and its correlation with clinical outcomes, endogenous antibody responses, pharmacokinetic properties of neutralizing mAbs and the potential benefit of combining antibodies to defend against emerging viral variants.

Tenforde, M.W., Olson, S.M., Self, W.H., Talbot, H.K., Lindsell, C.J., Steingrub, J.S., Shapiro, N.I., Ginde, A.A., Douin, D.J., Prekker, M.E., Brown, S.M., Peltan, I.D., Gong, M.N., Mohamed, A., Khan, A., Exline, M.C., Files, D.C., Gibbs, K.W., Stubblefield, W.B., Casey, J.D., Rice, T.W., Grijalva, C.G., Hager, D.N., Shehu, A., Qadir, N., Chang, S.Y., Wilson, J.G., Gaglani, M., Murthy, K., Calhoun, N., Monto, A.S., Martin, E.T., Malani, A., Zimmerman, R.K., Silveira, F.P., Middleton, D.B., Zhu, Y., Wyatt, D., Stephenson, M., Baughman, A., Womack, K.N., Hart, K.W., Kobayashi, M., Verani, J.R. and Patel, M.M. (2021). “Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Among Hospitalized Adults Aged ≥65 Years – United States, January-March 2021.” MMWR Morb Mortal Wkly Rep 70(18): 674-679.

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Adults aged ≥65 years are at increased risk for severe outcomes from COVID-19 and were identified as a priority group to receive the first COVID-19 vaccines approved for use under an Emergency Use Authorization (EUA) in the United States (1-3). In an evaluation at 24 hospitals in 14 states,* the effectiveness of partial or full vaccination(†) with Pfizer-BioNTech or Moderna vaccines against COVID-19-associated hospitalization was assessed among adults aged ≥65 years. Among 417 hospitalized adults aged ≥65 years (including 187 case-patients and 230 controls), the median age was 73 years, 48% were female, 73% were non-Hispanic White, 17% were non-Hispanic Black, 6% were Hispanic, and 4% lived in a long-term care facility. Adjusted vaccine effectiveness (VE) against COVID-19-associated hospitalization among adults aged ≥65 years was estimated to be 94% (95% confidence interval [CI] = 49%-99%) for full vaccination and 64% (95% CI = 28%-82%) for partial vaccination. These findings are consistent with efficacy determined from clinical trials in the subgroup of adults aged ≥65 years (4,5). This multisite U.S. evaluation under real-world conditions suggests that vaccination provided protection against COVID-19-associated hospitalization among adults aged ≥65 years. Vaccination is a critical tool for reducing severe COVID-19 in groups at high risk.